Biopsy site marker

ABSTRACT

A biopsy site marker configured to expand upon deployment into a biopsy cavity, and visible under several different imaging modalities, comprises a superabsorbent hydrogel component and a radiopaque element. The hydrogel is in a compressed, dehydrated state prior to deployment to facilitate placement of the marker within the biopsy site, and thereafter expands upon deployment in the biopsy site. Such expansion limits migration of the site marker.

FIELD OF INVENTION

The disclosed inventions relate generally to site markers for breastbiopsy procedures. More specifically, the disclosed inventions relate tosite markers that are visible under several different imagingmodalities.

BACKGROUND

In the diagnosis and treatment of breast cancer, it is often necessaryto perform a biopsy to remove tissue samples from a suspicious mass. Thesuspicious mass is typically discovered during a preliminary examinationinvolving visual examination, palpation, x-ray, magnetic resonanceimaging (MRI), ultrasound imaging or other detection means.

When a suspicious mass is detected, a sample is taken by biopsy, andthen tested to determine whether the mass is malignant or benign. Thisbiopsy procedure can be performed by an open surgical technique, orthrough the use of a specialized biopsy instrument. To minimize surgicalintrusion, a small specialized instrument such as a biopsy needle isinserted in the breast while the position of the needle is monitoredusing an imaging technique such as fluoroscopy, ultrasonic imaging,x-rays, MRI or other suitable imaging techniques.

In one biopsy procedure, referred to as stereotactic needle biopsy, thepatient lies on a special biopsy table with her breast compressedbetween the plates of a mammography apparatus and two separate X-raysare taken from two different points of reference. A computer thencalculates the exact position of the mass or lesion within the breast.The coordinates of the lesion are then programmed into a mechanicalstereotactic apparatus which advances the biopsy needle into the lesionwith precision. At least five biopsy samples are usually taken fromlocations around the lesion and one from the center of the lesion.

Regardless of the method or instrument used to perform the biopsy,subsequent examination of the surgical site may be necessary, either ina follow up examination or for treatment of a cancerous lesion.Treatment often includes a mastectomy, lumpectomy, radiation therapy, orchemotherapy procedure that requires the surgeon or radiologist todirect surgical or radiation treatment to the precise location of thelesion. Because this treatment might extend over days or weeks after thebiopsy procedure, by which time the original features of the tissue mayhave been removed or altered by the biopsy, it is desirable to insert asite marker into the surgical cavity to serve as a landmark for futureidentification of the location of the lesion.

Known biopsy site markers have been found to have disadvantages in thatthe site markers are not visible under all available imaging modalities.Moreover, because of this problem, when cancer is found at a biopsy sitethat has been previously marked with a site marker, due to the poorvisibility of the biopsy site marker under ultrasound or othervisualization modalities, or lack of differentiation between marker andanatomical features, the patient must undergo an additional procedurethat places an additional device within the biopsy site to enable thesurgeon to find the biopsy site during surgery. Limited visibility (ornone at all when using ultrasound) limits the ability to monitor tumorprogression or shrinkage during neo adjuvant chemotherapy with themarker serving as a reference point. One known technique has been toplace a breast lesion localization wire at the biopsy site. Thelocalization wire is typically placed at the biopsy site via mammographyand/or ultrasound.

Another issue that arises with site markers is migration. When the sitemarkers are typically deployed to the biopsy site, the breast is stillunder compression. However, when the breast is released fromcompression, the site marker may migrate within the site or even out ofthe site through a needle tract created by the biopsy device, therebypreventing a surgeon or radiologist from easily locating the preciselocation of the lesion or biopsied area.

Accordingly, there is a need for site markers made from biocompatiblematerials that are visible under various modes of imaging to reduce thenumber of procedures that patients must undergo in detection andtreatment of cancer. There is also a need to limit migration of a sitemarker when the site marker is placed in a biopsy site.

SUMMARY

In accordance with the disclosed inventions and embodiments thereof, aremotely detectable marker is provided for implantation in a targetedsite within a patient's body from which tissue has been removed, whereinthe marker comprises a radiopaque element having a distinguishingpattern for unique identification under x-ray imaging, and anon-palpable body coupled to the radiopaque marker. In one embodiment,the body is comprised of a substantially dehydrated material in apre-deployment configuration, wherein the body is configured to expandbetween 5 and 100 percent of its pre-deployment volume in approximately30 to 60 minutes when exposed to fluid, and to remain substantiallyphysically stable when implanted within the targeted site for at leastapproximately 52 weeks, wherein the body is configured to reflectultrasound in a way that the body is recognizable as being artificialand is distinguishable from the radiopaque marker. In one embodiment,the body is comprised of a substantially dehydrated material in apre-deployment configuration, wherein the body has a swell ratio of100-1000 wt/wt when exposed to fluid for approximately 30 to 60 minutes,and is configured to remain substantially physically stable whenimplanted within the targeted site for at least approximately 52 weeks,wherein the body is configured to reflect ultrasound in a way that thebody is recognizable as being artificial and is distinguishable from theradiopaque marker.

In various embodiments, the radiopaque element (which may be metallic orpolymeric) is be formed out of a braided, woven or mesh structuredefining an interior region, wherein the body is contained within theinterior region of the radiopaque element. In some embodiments, theradiopaque element is made out of PMMA or ultra-high molecular weightpolyethylene (UHMWPE) compounded with a radiopacifier. In one suchembodiment, the radiopaque element comprises PMMA that is loaded withapproximately 30% to approximately 70%, and more preferablyapproximately 60%, barium sulfate by weight. In another embodiment, theradiopaque element comprises PMMA that is loaded with approximately 17%to approximately 23%, and preferably approximately 20%, bismuth trioxideby weight. In various embodiments, the PMMA is configured to achievesimilar radiographic contrast as PEKK at a smaller volume than PEKK.

In various embodiments, the body of the marker is made out of ahydrogel, preferably configured minimize a specular appearance underultrasound when hydrated. In one such embodiment, the radiopaque elementcomprises PMMA, wherein the PMMA and hydrogel are configured to formcovalent crosslinks. In one such embodiment, the body comprises one ormore of pHEMA, PVP, PEGDA and PVA.

In various embodiments, the body of the marker is made out of ahydrogel, preferably configured minimize a specular appearance underultrasound when hydrated. In one such embodiment, the radiopaque elementcomprises PMMA, wherein the PMMA and hydrogel are configured to formcovalent crosslinks. In one such embodiment, the body comprises one ormore of pHEMA, PVP, PEGDA and PVA.

In various embodiments, the radiopaque element is formed by braidedNitinol tubing. In various embodiments, the radiopaque element is madefrom a shape memory material and/or a superelastic material. In oneembodiment, the radiopaque element is made from a radiopacifier-loadedfiber. In one embodiment, the body of the marker comprises a first layerfixedly coupled to a second layer, the first and second layers eachhaving a proximal end, wherein the respective proximal ends of the firstand second layers are substantially aligned, the first layer comprisinga thermoplastic and the second layer comprising of a substantiallydehydrated material that swells upon contact with fluid to cause thesecond layer to transition to a post-deployment configuration, thepost-deployment configuration having a distinguishing pattern. In suchembodiment, the radiopaque element may be disposed proximal to therespective proximal ends of the first and second layers. In suchembodiment, the second layer may be made out of shape memorythermoplastic.

Invarious embodiments, the body of the marker comprises a superabsorbentpolymer contained in a polymer mesh. By way of non-limiting example, thebody may be a folded or rolled polymer pouch containing the radiopaqueelement, wherein the pouch comprises a woven nylon mesh formed out ofpolyester thread filled with PVG/PEGDA granules. Alternatively, theradiopaque element may comprise PMMA or UHMWPE. In one embodiment, thepouch comprises a radiopaque fiber comprised of approximately 20 percentby weight bismuth trioxide.

Other and further aspects and features of the disclosed inventions willbe evident from reading the following detailed description of thepreferred embodiments, which are intended to illustrate, not limit, theinvention.

BRIEF DESCRIPTION OF THE DRAWINGS

The drawings illustrate the design and utility of the disclosedembodiments, in which similar elements are referred to by commonreference numerals. In order to better appreciate how the above-recitedand other advantages and objects of the disclosed embodiments areobtained, a more particular description is set forth by reference to theaccompanying drawings. Understanding that these drawings depictexemplary embodiments of the disclosed inventions, and are not thereforeto be considered limiting, the illustrated embodiments will be describedand explained with additional specificity and detail through the use ofthe accompanying drawings in which:

FIG. 1 is a perspective view of a biopsy site in a human breast showingthe breast in section and one or more site markers being implanted inthe biopsy cavity;

FIGS. 2A and 2C are plan views of a site marker according to a firstembodiment;

FIGS. 2B and 2D are cross-sectional views along lines 2B-2B and 2D-2D inFIGS. 2A and 2C, respectively;

FIG. 2E is a plan view of an alternate embodiment to FIGS. 2A-2D;

FIGS. 3A and 3B are perspective views of a site marker according to asecond embodiment in a dehydrated state, and a hydrated state,respectively;

FIG. 3C is an enlarged view of a portion of the second embodiment in thedehydrated state;

FIG. 3D is a cross-sectional view of the second embodiment along line3D-3D in FIG. 3C;

FIGS. 4A and 4B are perspective views of a site marker in an expandedstate and a contracted state, respectively, according to a thirdembodiment;

FIGS. 5A and 5B are plan views of a site marker in a dehydrated stateand a hydrated state, respectively, according to a fourth embodiment;

FIG. 6 is a plan view of a site marker according to a fifth embodiment;

FIGS. 6A and 6B are plan views of a delivery device prior to markerdeployment and after marker deployment, respectively; and

FIG. 7 is an alternate embodiment of a delivery device for the sitemarkers.

DETAILED DESCRIPTION OF THE ILLUSTRATED EMBODIMENTS

Biopsy markers are described herein for use in breast biopsy, but couldbe used in other areas. The markers described herein present asignificant performance change from existing technologies withoutsubstantially adding to the cost of this fundamentally high volumeproduct. Existing products provide an unacceptably short duration ofultrasound contrast and have been prone to migration from the originalbiopsy location due to a lack of tissue adhesion to cavity walls,mechanical attachment, or rapid expansion upon deployment. Thesedeficiencies suggest a new device comprised of a hydrogel, or similartechnology, surrounding a radiopaque core or a hydrogel contained withina flexible envelope.

Preferably, a biopsy site marker provides permanent radiographiccontrast and distinct ultrasound contrast for a minimum of one year(fifty-two weeks) within limited posterior acoustic shadowing. Theportion of the marker providing ultrasound contrast may be eitherpermanent or biodegradable. The marker preferably has a “man-made” shapeto clearly differentiate it from other biological structure and abnormalfeatures. The permanent portion of the marker preferably sits in themiddle of the cavity. The marker is preferably configured to minimizemigration and improve tissue adhesion relative to existing cavitystructure. The marker preferably swells to fill the biopsy cavity, yetnot swell so much that it is palpable by the patient. Delivery of themarker is preferably single-handed and as simple as possible. The shelflife is preferably at least two years.

FIG. 1 illustrates a perspective view of a human breast 10 beingimplanted with a site marker 12 according an embodiment of thedisclosure. At a biopsy site 14 is a lesion 16 from which a tissuesample has been removed, resulting in a biopsy cavity 18. One or moresite markers 12 are implanted in the biopsy cavity 18 using a markerdelivery system 20. In one embodiment, the marker delivery system 20advanced by sliding it through an inner lumen 22 of a biopsy device (notshown), which avoids the need to withdraw the biopsy device andthereafter insert the marker delivery system 20. Delivering the sitemarker 12 in the biopsy cavity 18 without withdrawing the biopsy devicereduces the amount of tissue damage and enables more accurate placementof the site marker 12. The marker delivery system 20 illustrated in FIG.1 is exemplary only and it is understood that the site markerembodiments disclosed herein are suitable for use with other markerdelivery systems.

FIGS. 2A-5B illustrate various exemplary site marker embodimentsaccording to the present disclosure. In general, the site markersdescribed herein are made from biocompatible materials that haveappropriate densities for radiographic imaging, appropriate surfacecharacteristics, and acoustic impedance differences for ultrasonicimaging, and appropriate magnetic characteristics for magnetic resonanceimaging. The constituent materials of the site markers are either notbiodegradable or can be tuned to degrade over a long time scale. Thefifty-two week scale encompasses a typical timespan in which a physicianwould need visibility of the marker to be able to monitor a full roundof neo adjuvant chemo therapy, in order to reduce the tumorsignificantly leading to lumpectomy. In particular, uniformity ofacoustic impedance in the marker is highly desirable. A strong impedancemismatch will result in a clear outline using ultrasound, and theability of the hydrogels described herein to maintain a constantimpedance throughout yields a “clean” and speckle-free image, whereas ahydrogel with heterogenous impedance would yield a speckled image, andmay be mistaken for tissue, which is further discussed below.

The site markers disclosed herein in the pre-deployment state are solidcompacted structures, in dehydrated states reduced in size from theirdesired final state. These markers also have a distinct 3D configurationin a hydrated state. Upon deployment in a biopsy cavity, the markers areconfigured to expand in situ immediately and reach full size withinthirty to sixty minutes. The markers may expand axially (in height) andlongitudinally (in width) to a size that is larger than the initial sizeof the biopsy tract. Preferably, the fully expanded marker occupies morethan 50% of the diameter of the biopsy cavity. This expansion can betailored based on the type of polymer used for the superabsorbenthydrogel, the conditions under which the polymer has been prepared(e.g., different processing conditions which may influence e.g.crosslink density and affect swell ratio/swell kinetics), the surfacearea of the polymer, swelling rate of the polymer, the give orelasticity of a polymer/metal envelope that contains the hydrogelpolymer, the processing conditions to set the final/expanded shape andits final dimensions, the amount of saline used for deployment, and theamount of bodily fluids within the biopsy cavity. This tailoredexpansion could aid in precise marking of the lesion and precisedeployment, and preventing the marker from being displaced within thebiopsy cavity or biopsy track. The time frame of sixty minutes allows aradiologist to confirm placement after deployment using any imagingmodality, and to confirm placement with a mammogram shortly after themarker is deployed. In particular, the markers will start to becomevisible under U/S and MRI within minutes, and will reach their “final”deployed state within an hour of being deployed in the patient's bodyThis is routine practice as radiologists image at deployment and confirmwith a mammogram before a patient leaves the facility. A fully expandedmarker preferably has a non-palpable feel at deployment, and in the longterm due to the selection of biocompatible materials should trigger aminor tissue inflammatory response with minimal scar formation.

In one embodiment, shown in FIGS. 2A-2D, a gel mesh biopsy marker 200includes a polymer mesh pouch or envelope 202, superabsorbent hydrogelgranules 204 disposed within the pouch 202, and a radiopaque element 206disposed within the pouch 202. Prior to deployment in a biopsy cavity,the gel granules 204 are in a dehydrated state and the mesh pouch 202 isrelatively flat, as shown in FIGS. 2A and 2B. When the granules 204 aredehydrated, the gel mesh biopsy marker 200 may be rolled or folded fordelivery into the biopsy cavity. Upon deployment into the biopsy cavity,the pouch 202 immediately unrolls or unfolds to lie flat. Thisunrolling, or unfolding, increases the width of the marker 200, makingit unlikely that the marker 200 can migrate along the biopsy cavity.

Upon delivery to the biopsy cavity, the hydrogel granules 204 absorbliquid. For example, the marker deployment process may include a salinewash to accelerate hydration of the granules 204, wherein the salinewash is intended to accelerate the hydration/expansion and allow for amore predictable deployment behavior (i.e. more predictable hydrationkinetics, time from deployment to first visibility under U/S or MRI).But even without the saline wash, the hydrogel component will absorbphysiological fluids (blood, interstitial fluid), as further discussedherein. During the liquid absorption, the granules 204 swell to expandand fill the pouch 202, as shown in FIGS. 2C and 2D. Depending on theconditions of the deployment, the gel mesh marker 200 may expand fullywithin approximately 10 minutes. The expansion is limited by thehydrogel loading, hydrogel chemistry and the dimensions, give orelasticity the mesh pouch 202. The surface area and elasticity of themesh pouch 202 defines the maximum possible displacement, while thequantity of gel granules 204 within the pouch 202 defines the actualdisplacement and the stiffness of the fully swollen marker 200. Markerexpansion therefore occurs by two mechanisms—mesh pouchunfolding/unrolling and water absorption by the gel granules 204.

The mesh pouch 202 may be made of a polymer, such as nylon. The meshpouch 202 may be a woven nylon mesh sewn, by way of non-limitingexample, into a rectangular patch geometry using polyester thread. Otherpatch geometries are also possible, and the patch may also be assembledvia techniques other than sewing, such as by ultrasonic or thermalwelding The mesh is a fine mesh that prevents the granules 204 fromescaping through the holes in the mesh in either the dry or hydratedstate. In other words, the openings in the mesh are significantlysmaller than the granules 204. Further, the hydrogel granules in thehydrated state are sufficiently rigid (i.e., have a high enough modulusor physical integrity) to prevent being “squeezed” out through the poresunder physiological loads expected within the biopsy cavity.

The granules 204 may be superabsorbent hydrogel granules. For example,the granules 204 may be made of a co-polymer of polyvinylpyrrolidone andpoly(ethylene glycol) diacrylate (PVP/PEGDA) that provides ultrasoundand MRI contrast. In one embodiment, the hydrogel granules are aPVP/PEGDA gel prepared with the following formulation: 15% vinylpyrrolidone, 7.5% poly(ethylene glycol) dimethyacrylate (700 g/mol), and1% sodium chloride in water. Relative to the monomer content, 1%2,2-dimethoxy-2-phenylactophenone may be added as a photoinitiator toenable crosslinking via ultraviolet radiation. The resulting formulationmay be UV cured in a polystyrene petri dish for approximately 20 minutes(e.g., with a light source of approximately 48 W, and approximately 254nm). After this time, the gel may be swollen in distilled waterovernight to remove unreacted products, then dried at 80° C. forapproximately 8 hours to remove the water. The gel may then be groundusing a grinder and the resulting material may be sieved to yieldgranules 204 of approximately 50-100 μm in size, which are loaded intothe polymer mesh pouch 202 prior to closure with the polyester thread.

The radiopaque element 206 may comprise a poly(methyl methacrylate)(PMMA) shape loaded with radiopacifier. The PMMA can easily be formedinto unique shapes via molding or die extrusion, for example. Such aunique shape would allow for easy identification under x-ray imaging.Material radiopacity and density of PMMA in the current configurationlimits or eliminates the traditional black artifact that surrounds metalbased markers when visualized under mammography and tomosynthesis. Theseartifacts could lead to a misrepresentation of an anatomical featuresurrounding the marker. Thus PMMA allows easier identification of themarker permanently without limiting surround anatomy or lesion ofinterest. In one embodiment, the radiopaque element 206 used in the gelmesh marker 200 is a cylindrical PMMA marker approximately 400 μm indiameter. For example, KYPHON HV-R bone cement powder and liquidcomponents, modified to yield a 60% wt/wt barium sulfate concentration,may be mixed for approximately sixty seconds and then extruded through a22 gauge needle onto a polyethylene surface and cut into approximately 3mm long sections. These radiopaque elements 206 may be loaded into themesh pouch 202 together with the hydrogel granules 204.

In another embodiment, the radiopaque element may be attached to thepouch 202 rather than contained within the pouch 202. For example, asshown in FIG. 2E, a radiopaque thread 206′ embroidered into the meshpouch 202 serves as the radiopaque element. Alternatively oradditionally, the radiopaque thread 206′ could be used to design acustom mesh that incorporates the thread 206′ into the mesh itself inidentifiable patterns. For example, the radiopaque thread 206′ may be aradiopaque fiber (e.g., Dyneema Purity® (DSM)) incorporated into the gelmesh marker 200′ to provide contrast when viewed using x-ray imaging.The radiopaque fiber 206′ may be a medical grade ultra-high molecularweight polyethylene (UHMWPE) loaded with approximately 20% bismuthtrioxide by weight. Embroidery of the fiber 206′ into the mesh 202, orincorporating the fiber as part of the mesh, ensures attachment of thefiber 206′ to the mesh 202 and allows patterning for uniqueidentification.

The gel mesh marker 200 has been shown to be visible under severaldifferent imaging modalities. During ultrasound imaging, the watercontent of the hydrogel component 204 provides a hypoechoic region,distinctly outlined by hyperechoic polymer mesh 202. Some optimizationof hydrogel loading may be required in order to ensure complete materialhydration at equilibrium (partially hydrated hydrogel particles resultin a “specular” appearance which reduces overall marker contrast). X-rayvisibility is achieved by the inclusion of the radiopaque polymerelement 206, 206′ inside or on the surface of the polymer pouch 202.Under MRI imaging (wherein the mechanism for the MRI contrast is thehigh relative water content of the hydrogel relative to surroundingtissue), the hydrogel 204 contained within the gel mesh marker 200appears as a bright shape (signal enhancement) in the T2 weighted imagesequence and as a dark shape under T1 weighted image sequences.Alternatively, it may be desirable to create a specular appearance withdistinct ‘big bubbles’ or other types of artifacts that remainpermanently visible, e.g., like a signature, to make it easier todifferentiate as a man-made structure.

In another embodiment, shown in FIGS. 3A-3D, a biopsy marker 300comprises a bilayer composite material that resembles a curly fry in thehydrated state, which is shown in FIG. 3B. The curly fry biopsy marker300 starts off as a flat strip (FIG. 3A) comprising a superabsorbenthydrogel layer 302 in a dehydrated state and a mesh layer imbibed withhydrogel 304, forming a continuous gel network through the thickness ofthe biopsy marker 300. Upon hydration, the superabsorbent hydrogel layer302 swells to a higher degree than the mesh layer 304, although the mesh304 does not swell to any significant degree. In particular, the mesh304 constricts the hydrogel swelling, and is deformed by the hydrogel ina manner that is dependent on the mesh properties (e.g. anisotropy inextensibility, pore geometry) and the mechanical properties of thehydrogel. The nonhomogeneous expansion results in curling to a helicalgeometry. The high swell ratio of the hydrogel layer 302 enablesspace-filling expansion and (under some modalities) imaging contrast.The curly fry biopsy marker 300 may be delivered into the biopsy cavity,deploying in response to hydration. Alternatively or additionally, themarker 300 may be placed in a cannula for delivery and expelled using apush rod to deploy. A backflush with saline or water may be used toensure a rapid rate of swelling.

The initial marker 300 may be rectangular in shape with approximatedimensions of 3 cm length×0.1 cm width×0.05 cm thickness. As thehydrogel 302 absorbs water and swells, the biopsy marker 300 curls,forming a helical geometry, aka, “curly fry” shape. This curly fry shapechange is diffusion limited, and is triggered once the bulk hydrogelsoftens. The curling may begin within 3-5 minutes after exposure towater, and the final geometry may be attained in approximately 30minutes. More rapid shape change may be achieved by deploying the marker300 in the hydrated or partially hydrated state, or by adjusting thehydrogel formulation. The final size of the marker 300 is approximately1.0 cm length×0.5 cm diameter. Thus, the overall length of the marker300 decreases upon hydration, but the effective diameter increasessignificantly. The swelling and resulting diameter growth may fill thebiopsy cavity and localize the marker 300 to the biopsy site.

As such, in addition to hydrogel expansion, the curly fry marker 300incorporates a shape transforming mechanism to assist in filling thebiopsy cavity and in preventing migration. In particular, the curly frymarker 300 transforms from essentially a 2D strip to a 3D (curled)structure. The final 3D helix, which is only achieved upon hydration ofthe gel 302, assists in preventing the migration of the marker 300 fromthe biopsy site. Each ring or curl within the helix is substantiallyaligned concentrically making it stay within a cylinder like structure.However, depending of the mesh orientation, configuration, andprocessing of the bulk hydrogel, or by having different blocks ofhydrogel chemistries embedded in the mesh), individual rings or curls ofthe helix may be offset from the central axis, creating a“discontinuous” curly fry structure with protruding rings/curls thatfunction somewhat like a threaded screw to aid in keeping the markerconfined at the site of implantation. In particular, the 3D helixhydrogel geometry can be adjusted through control of the mesh andhydrogel properties. For example, positioning blocks of hydrogels withdifferent chemistries along the length of the biopsy marker could leadto variable curvature in the deployed state. In such a case, thediameter of the helix could vary along the length or reach a maximum inthe center of the marker. Similar diameter variation could be obtainedthrough control of the relative thickness of the hydrogel and imbibedmesh layers. For instance, with a constant hydrogel layer thickness, athicker mesh layer would have a larger curled diameter due to increasedstiffness and resistance to curling. Variation of the mesh orientationalong the length of the biopsy marker could lead to a variable pitchalong the length of the curled 3D helix. Further, adding additionalstructural features to the mesh (e.g. creasing, folding, thermal welds),may allow a change of the angle of the central axis of the helix.

A limitation of a bilayer design can be the adhesion between plies. Asthe curly fry marker 300 relies on nonhomogeneous swelling, inherentstresses at the boundary between layers 302 and 304 in the curled markermay cause delamination at the interface between the non-swelling andswelling layers. The mesh 304 may alleviate this issue, as the hydrogelprecursor infiltrates the mesh 304, as shown in FIGS. 3C and 3D,allowing more continuity of the hydrogel 302 through the thickness ofthe marker 300. With excess hydrogel 302 on one surface, the compositebecomes a bilayer structure with a hydrogel layer 302 and a layer ofmesh 304 embedded in hydrogel 302. Such interpenetration of the hydrogel302 may allow for good adhesion between the layers 302 and 304, limitingdelamination effects.

In order to obtain pitch in the curling of the bilayer marker 300, themesh 304 may be formed of a material that elastically deforms in ananisotropic manner. Specifically, the mesh 304 may stretch more in onedirection than in the perpendicular direction. The relative differencein stretch between the two directions, along with the orientation of themesh 304 in the marker 300, dictates the final geometry of the curledbiopsy marker 300. A mesh without this anisotropy may enable curling,but with zero pitch.

In one embodiment, the curly fry marker 300 incorporates a radiopaqueelement in the form of a thread 306 that is embroidered into the mesh304. Alternatively or additionally, the radiopaque thread 306 may beused to design a custom mesh that incorporates the thread inidentifiable patterns.

The curly fry marker 300 preferably includes a hydrogel component 302that has a high swell ratio and is tough, deformable, and resistant tocrack propagation. To achieve these properties, a poly(vinylpyrrolidone-co-ethylene glycol dimethacrylate)/poly(vinyl alcohol) blend(PVPEGDA/PVA) may be used as the hydrogel 302. PVPEGDA alone has a highswell ratio, but is highly notch sensitive. Such a property is not idealfor the curly fry marker 300, as the boundaries between the mesh 304 andthe gel 302 can serve as sites for crack initiation. PVA is a hydrogelknown for its toughness, though alone, may be too stiff for the curlyfry marker 300, and the swelling is not completely reversible. Combined,the PVPEGDA/PVA is more resistant to crack propagation and can bereversibly swelled in water or saline.

The PVPEGDA/PVA gel may be prepared with the following formulation: 15%vinyl pyrrolidone, 5% poly(ethylene glycol) dimethacrylate (700 g/mol),5% poly(vinyl alcohol) (106,000-110,000 g/mol, 99.3+super hydrolyzed),and 1% sodium chloride in water. Relative to the monomer content, 1%2,2-dimethoxy-2-phenylactophenone may be added as a photoinitiator toenable crosslinking via ultraviolet radiation.

The mesh layer 304 may be a polyester mesh with a negligible swellresponse in water. Polyesters are widely used in medical applicationsand typically, are not biodegradable. For example, when considering longterm contrast created by the mesh, the mesh layer 304 may comprisepoly(ethylene terephthalate), or PET, which is used frequently inbiomedical materials, in particular sutures, tendon reconstruction,vascular grafts, and surgical meshes, and PET is resistant to biologicaldegradation, so the mechanical properties and imaging contrast may bestable for more than a year. Notably, long term contrast created by thehydrogel will be dependent on the stability of the hydrogel.

The radiopaque element 306 used in the curly fry marker 300 may be aradiopaque fiber similar to the fiber 206′ described above with respectto the gel mesh marker 200. The fiber 306 may be attached to the mesh304 prior to imbibing in the hydrogel 302 to ensure attachment to themarker 300. The mesh 304 with the attached radiopaque fiber 306 may beimbibed with the PVPEGDA/PVA hydrogel 302 to form the biopsy marker 300.

The curly fry biopsy marker 300 has been shown to be visible underseveral different imaging modalities. While the water content in thehydrogel 302 is expected to provide strong ultrasound contrast, theresulting signal under this imaging modality is complex. Due to thethree dimensional folded structure of the bilayer marker 300, theresulting signal may show a clear hypoechoic border around thehyperechoic mesh 304 but overall appearing as a discontinuous shape withsome posterior acoustic shadowing. Exemplary x-ray contrast was providedvia the radiopaque UHMWPE fiber 306 attached to the mesh component 304.The water content of the hydrogel component 302 provided excellent MRIcontrast, appearing as a bright white region in the T2 weighted scansand as a dark shape under T1 and fat suppression image sequences.

In another embodiment, shown in FIGS. 4A and 4B, a shape memory-basedbiopsy marker 400 comprises a cage 402 surrounding a superabsorbenthydrogel core 404. The cage 402 may have a torpedo-like or teardrop-likeshape, and comprises a superelastic shape memory material. For example,the cage 402 may be made of Nitinol. The marker 400 further includescrimp beads 406 at either end of the cage 402. The crimp beads 406 maybe metallic, or alternatively made of a polymer, and are used to closeoff the respective ends of the Nitinol cage 402, thereby enclosing thehydrogel component 404 within the cage 402 to provide unique X-rayidentification. It will be appreciated that other means may be employedto close off the ends of the cage 402, such as welding or knotting, thelatter of which may for example be realized by a drawstring and cinchmechanism. After the hydrogel core 404 is positioned within the cage402, the ends of the cage 402 may be closed off with the crimp beads406. In some embodiments, the crimp beads 406 are metallic, and maycomprise titanium, gold, silver, or the like. In one example, theNitinol cage 402 may be radially compressed and threaded through a 0.8mm silver plated brass crimp bead 406. In such embodiments, the metalliccomposition of the crimp bead 406 may provide further radiographiccontrast with minimal to no MRI artifacts. Alternatively, the cage 402may be constructed using Nitinol having a shape transition temperatureapproximately the same as body temperature, and flushing with warm/hotsaline to trigger a thermal transition, i.e. thereby relying on the trueshape memory mechanism, rather than rely on superelasticity.

Nitinol is the preferable shape memory material for the cage 402 due toits robust shape memory properties and the ability to tune theactivating temperature through composition. In one example, thecage-like structure 402 is made of braided Nitinol tubing. The braidingtechnique may impart desirable properties in the 3D tubing construct.Specifically, the Nitinol tubing is highly compressible through radialcompression and highly expandable through axial compression. Afterrelease of either the radial or axial compressive force, the Nitinoltubing elastically contracts to its native state. The extreme diameterchanges result from the braided geometry. Properties such as the maximumouter diameter, the braid density, and the elastic response of thetubing can be adjusted through the braiding parameters.

The superelasticity of the Nitinol may be utilized as a means forcompact delivery in a small diameter cannula and rapid space fillingupon deployment in the biopsy cavity. The Nitinol cage 402 may be set toa permanent expanded shape with a desired tapering diameter and adesired length. For example, the diameter of the cage 402 may beapproximately 0.5 cm at the maximum point, and the length of the cage402 may be approximately 1.0 cm. The shape memory marker 400 may becompressed to a smaller diameter such that the Nitinol tubing formingthe cage 402 are in contact with the hydrogel core 404. In this form,the shape memory marker 400 is easily inserted into a cannula 408 fordeployment, as shown in FIG. 4B. The size of the cannula 408 istherefore likely limited by the diameter of the hydrogel component 404,although the profile of the crimp beads 406 or alternative cage sealingmaterial, as well as the diameter of the Nitinol tubing/wire forming thebraid may also limit cannula size. The shape memory marker 400 may beextruded into the biopsy cavity using a simple push rod, and may be backflushed with saline to accelerate swelling of the hydrogel 404. Uponexiting the cannula 408, immediate elastic expansion assists in precisemarking of lesion, localizing the marker 400 and preventing migrationfrom the biopsy site. In addition, the torpedo-like shape may helpprevent migration of the marker 400 along the biopsy tract duringretraction of the cannula 408. As a larger diameter in the distalportion of the marker, prevents marker migration in the direction ofleast resistance such as the biopsy tract.

The hydrogel core 404 in the shape memory marker 400 provides ultrasoundand MRI contrast. The hydrogel core 404 may, for example, beapproximately 0.5 cm long and 0.8 mm in diameter in the dehydratedstate. In one embodiment, the hydrogel 404 is a poly(vinylpyrrolidone-co-ethylene glycol dimethacrylate) (PVPEGDA) gel preparedwith the following formulation: 7.5% vinyl pyrrolidone, 2.5%poly(ethylene glycol) dimethyacrylate (700 g/mol), and 1% sodiumchloride in water. Relative to the monomer content, 1%2,2-dimethoxy-2-phenylactophenone may be added as a photoinitiator toenable crosslinking via ultraviolet radiation. The resulting formulationmay be cast in quartz tubing (e.g., 2.3 mm nominal ID) to obtaincylindrical hydrogel rods. Lower overall monomer content was used forthe hydrogel component 404 of the shape memory marker 400 compared tothe hydrogels used in the other marker embodiments. The lower monomercontent allows for a higher swell ratio, but reduces the mechanicalstrength of the gel in the swollen state. The shape memory marker designencapsulates the hydrogel 404 within a cage structure 402, and thus,does not rely on mechanical strength of the hydrogel 404 duringpotential marker removal.

The shape memory marker 400 is distinct from the other markerembodiments in that no radiopaque element was added solely for thepurpose of imaging contrast. In some embodiments, the Nitinol cage 402and the crimp beads 406 are metallic and inherently radiopaque.Adjustment of the permanent shape of the Nitinol cage 402 or the size,shape, or number of the crimp beads 406 may enable differentiationbetween multiple biopsy sites.

The shape memory marker 400 (including the crimp beads 406) may becoated with a thin hydrogel layer (e.g., polyethylene glycol (PEG) orthe like) or other low friction materials (e.g. ePTFE, silicone,poly(glycerol sebacate) PGS) that may aid in reducing friction of theshape memory marker 400 upon deployment. Such a coating may facilitatedeployment of the shape memory marker 400 out of the distal end of adelivery device, and may also prevent shredding of the cage 402 due tofriction between the outer surface of the cage 402 and the inner surfaceof a delivery cannula. This coating may also provide another enhancementfor ultrasound visualization. Alternate deployment strategies (e.g.using a soluble plug—discussed below) may also prevent damage to themarker during deployment.

The shape memory marker 400 has been shown to be visible under severaldifferent imaging modalities. For example, ultrasound imaging of theshape memory marker 400 demonstrated distinct echogenic contrast betweenthe hyperechoic Nitinol edge and hypoechoic hydrogel interior. Theresulting effect is a dark interior shape with a bright “outline” whenviewed in cross-section. The Nitinol wire configuration is easilyvisualized as a thin hyperechoic crisscrossed structure with ahypoechoic background when the ultrasound transducer is scanned of themarker. The crimp beads 406 (which may be composed of silver platedbrass, for example) on either end of the cage 402 also provide distincthyperechoic contrast. The fully deployed shape memory biopsy marker 400is visible under x-ray, which clearly captures the Nitinol wire in thebraided shape of the cage 402 as well as the crimp beads 406 on eitherside of the marker 400. Due to the thin wire diameter, the marker 400does not mask tissue behind the marker 400 and surrounding media, and assuch the marker 400 appears translucent (a.k.a, a “mesh screen” effect).Both the Nitinol and hydrogel components are identifiable using MRI. TheNitinol cage 402 appears as a dark outline around the bright hydrogelcore 404 in T2 weighted images. In T1 weighted images, the entire marker400 appears as a dark region.

In yet another embodiment, shown in FIGS. 5A and 5B, a swelling beadbiopsy marker 500 comprises a solid radiopaque core 506 coated with asuperabsorbent polymer hydrogel 504. The swelling bead marker 500 isdelivered to the biopsy cavity with the hydrogel 504 in a dehydratedstate, and the hydrogel 504 expands upon delivery into the biopsycavity. Marker deployment may include a saline wash to acceleratehydration of the hydrogel 504.

In order to achieve x-ray contrast, the radiopaque core 506 may comprisea PMMA shape loaded with radiopacifier. The PMMA can easily be formedinto unique shapes via molding or die extrusion, for example. Forexample, the radiopaque element 506 used in the swelling bead marker 500may be a cylindrical PMMA marker approximately 400 μm in diameterprepared in the same manner as the radiopaque element 206 describedabove with respect to the gel mesh marker 200. The PMMA core 506 may behard and rigid, while the hydrogel 504 may be soft and brittle. Thecompatibility of the PMMA chemistry with the hydrogel 504 may result inchemical bonds being formed between the hydrogel 504 and the PMMA core506 during curing. In particular, if the hydrogel chemistry is chosencarefully and/or if the underlying radiopaque element has undergoneappropriate surface treatment e.g. functionalization/silane modificationof a metallic radiopaque marker, then covalent chemical bonding mayoccur during polymerization of the hydrogel material, occurring betweenthe hydrogel material and the radiopaque element, improving adhesionbetween these two dissimilar materials.

The hydrogel component 504 in the swelling bead marker 500 providesultrasound and MRI contrast. In one embodiment, the hydrogel 504 is aPVP/PEGDA gel prepared with the following formulation: 15% vinylpyrrolidone, 7.5% poly(ethylene glycol) dimethyacrylate (700 g/mol), and1% sodium chloride in water. Relative to the monomer content, 1%2,2-dimethoxy-2-phenylactophenone may be added as a photoinitiator toenable crosslinking via ultraviolet radiation. The resulting formulationmay be UV cured in a half filled 2 mm diameter cylindrical quartz moldsealed with parafilm for approximately sixty seconds (the light sourcemay be, for example, approximately 48 W, and approximately 254 nm).Alternatively, a 1 mm diameter quartz mold may be employed for a smallermarker diameter. After this time, the radiopaque marker 506 (e.g., PMMA,60% barium sulfate wt/wt) may be loaded into the center of the hydrogeland the remainder of the quartz mold may be filled with gel precursorsolution. The resulting gel may be UV cured for an additional 15minutes. The gel may be extruded from the quartz mold and swollen indistilled water to remove unreacted products, then dried at 80° C. toremove the water prior to loading into a delivery device. Thismulti-step curing process specifically allows for the radiopaque elementto be positioned and correctly oriented in the center of the surroundinghydrogel.

The swelling bead marker 500 has been shown to be visible under severaldifferent imaging modalities. During ultrasound imaging, the swellingbead marker 500 is hypoechoic with a clear, sharp boundary around themarker 500, with hyperechoic radiopaque element 506 located inside.X-ray visibility is achieved by the inclusion of the radiopaque element506. Under MRI, the marker 500 appears as a bright shape in a T2weighted image sequence and as a dark shape under T1 and fat suppressionimage sequences. The smooth edges of the swelling bead marker 500clearly distinguish the marker 500 as man-made.

In another embodiment, shown in FIG. 6, a biopsy marker 600 comprises afoam material 602, a sticky coating 604, and a radiopaque element 606.Prior to deployment, the foam marker 600 comprises compressed,pre-shaped foam 602. As shown in FIG. 6, the foam 602 has a zig zagpattern to allow for the marker to be folded down for loading into thedelivery device and subsequent expansion/unfolding upon delivery, but itshould be readily understood that any shape may be used. Thecompressibility of the foam 602 allows for deployment in a reduced sizestate, and upon deployment the foam 602 may expand, unfold and fill inthe biopsy cavity. The foam 602 may preferably be saturated with fluidupon deployment, so as to retain more fluid, thereby reducing aircontent and shadowing. Alternatively or additionally, the foam 602 maybe pre-soaked with fluid and then deployed.

The foam 602 may be an open cell foam (e.g., silicone elastomer) or aclosed cell foam (e.g., polyethylene and/or silicone, textured silicone,etc.). In one example, the foam 602 is a closed cell polyester, meaningthat the polymer structure will contain entrapped air that will increaseultrasound contrast due to impedance mismatch, MRI contrast due to lackof signal from within the foam cells, and overall signal permanence dueto a lack of tissue ingrowth.

The foam 602 may be coated with a sticky coating 604 (e.g., a lowmolecular weight PEG, mucoadhesive hydrogel such as a thiolated PVAhydrogel, or the like) to aid in adhesion to the cavity walls, which mayreduce migration. Although FIG. 6 depicts the coating 604 outlining thefoam 602, it should be readily understood that the coating 604 coversthe entire outer surface of the foam 602. In one embodiment, the foam602 is dip-coated in a low molecular weight PEG (e.g., 2000 g/mol),which is solid at room temperature and body temperature but tacky due tothe sub ambient glass transition temperature of the material. The foam602 may undergo a single coating process in a solution of 30% PEG inisopropyl alcohol heated to 80° C.

The radiopaque element 606 may be (without limitation) made of titanium,which has been used in FDA-cleared permanent implants. The titanium wiremay be shaped into a unique form to further act as an identifier for thefoam biopsy marker 600. Multiple shapes could be used to enabledistinction between biopsy sites.

As shown in FIGS. 7A and 7B, the biopsy markers described above may bedelivered by a delivery device 700 that comprises a cannula 702 with anattached syringe 704 for back flushing with saline 708 and a push rod706 for deploying the markers. Although FIGS. 7A and 7B depict the shapememory marker 400 being deployed, it should be well understood that thedelivery device 700 may be used to deliver any of the site markersdescribed above. All of the marker embodiments include a hydrogelcomponent that is designed to provide ultrasound contrast and to assistwith migration prevention through swelling and filling a biopsy cavity710. As such, rapid swelling is preferable for immediate ultrasoundimaging capabilities and prevention of migration during delivery cannula702 retraction. The addition of excess saline 708 upon marker deploymentaccelerates the swelling process and provides improved ultrasoundcontrast.

The delivery device 700 allows a one-step deployment that accomplishesdelivery of the marker 400 as well as the addition of saline 708 to thebiopsy site 710. The biopsy marker 400 may be pre-loaded in the deliverycannula 702, as shown in FIG. 7A. The syringe 704 with the attached pushrod 706 may be filled with saline 708 to a desired volume and attachedto the cannula 702 containing the marker. Such attachment may be astandard Leuer lock twist fit, or a custom attachment. After positioningthe cannula 702 at the biopsy cavity 710, simply pushing the syringeplunger advances the push rod 706, which pushes the biopsy marker 400into the cavity 610, as shown in FIG. 7B. Simultaneously, saline 708 canbe delivered to the biopsy site 710. As shown in greater detail in FIG.7B, the inner push rod 706 is sized such that the outer diameter isslightly smaller than the inner diameter of the cannula 702, whichallows the flow of saline 708 between the push rod surface and thecannula 702.

Having separate cannulas and syringes may allow for sale of theindividual components, further minimizing the cost of the marker. Themarker could be sold within a disposable cannula, ready for deployment,and medical facilities could have one or more attachable syringe deviceson hand.

In another embodiment, shown in FIG. 8, a delivery device 800 comprisesa water soluble pellet 808 (e.g., composed of sucrose, PEG, or the like)rather than a push rod. The water soluble pellet 808 is positioned in acannula 802 between the biopsy marker 400 and saline 804, and is forcedforward by fluid pressure during depression of the syringe plunger (notshown). The plunger displaces the biopsy marker 400 into the biopsycavity as well as the water soluble pellet 808, which will eventuallydissolve. Once the water soluble pellet 808 is displaced into the biopsycavity, the saline solution 804 is free to fill the cavity andcontribute to hydration of the biopsy marker 400. An advantage of thisembodiment is that the soluble pellet 808 distributes the force of thedeployment and reduces possibility for damage to the biopsy marker.

Each of the embodiments described above with reference to FIGS. 2A-6comprises a hydrogel for enhanced ultrasound and MRI contrast and forlimiting marker migration. The expansion behavior post deployment servesto center the marker within the biopsy cavity and prevent migration. Thehydrogel is castable/moldable which allows for the marker to bemanufactured in a variety of shapes. The hydrogel may be loaded withother additives such as radiopacifiers and can potentially be bonded tounderlying substrates depending on their surface chemistry.

The swelling kinetics of the hydrogel components differ between the gelmesh marker 200 and the other three marker embodiments due to thesurface to volume ratio. The higher surface to volume ratio of thehydrogel granules 204 in the gel mesh marker 200 allows more rapidswelling to equilibrium. The swelling bead marker 500, curly fry marker300, and shape memory marker 400, while slower at reaching theequilibrium swell state, will immediately absorb water and form ahydrated shell around a dehydrated core. As such, all markers describedabove should be visible under ultrasound and MRI shortly afterdeployment, but only the gel mesh marker 200 may be in its final stateapproximately 10 minutes after deployment. The other markers 300, 400,and 500 may require about an hour to reach full hydration.

The hydrogel may be composed of polyacrylamide. Polyacrylamide hydrogelscommonly have swell ratios in the range of 100-1000 (wt/wt), and a500-1000 μm dry bead may swell up to 1-2 cm in size depending on thenature of the aqueous solvent (e.g., pH, salt content). The mechanicalproperties of the polyacrylamide may be adjusted by tuning the crosslinkdensity, resulting in a softer or more firm gel upon full hydration.Polyacrylamide is resistant to biological degradation, so the propertiesand imaging contrast should be stable for more than fifty-two weeks. Theswelling kinetics of polyacrylamide will depend on the surface area tovolume ratio of the material. As the surface area to volume ratioincreases (which will be generally true for smaller markers), the timerequired to reach an equilibrium volume will decrease. The material usedfor the hydrogel may also be a combination of one or more of:poly(2-hydroxyethyl methacrylate) (pHEMA), polyvinylpyrrolidone (PVP),poly(ethylene glycol) diacrylate (PEGDA), poly(vinyl alcohol) (PVA). Forexample, the swelling bead marker 500, gel mesh marker 200, and shapememory marker 400 may employ a co-polymer of PVP/PEGDA, while the curlyfry marker 300 may employ a co-polymer of PVP/PEGDA/PVA. It should beappreciated that material selection may affect reaction to biologicalfluids. Certain materials (e.g. polyacrylamide) will be sensitive to theionic character of the surrounding fluid and will exhibit differentswell ratios (and therefore imaging contrast by U/S and MRI) whenexposed to blood vs interstitial fluid vs DI water. Selecting a materialthat is relatively insensitive to ionic character of the surroundingfluid (e.g. as the PVP/PEGDA and PVP/PEGDA/PVA) ensures a morepredictable and consistent response during end use.

Once a material or materials are selected, many variables remain whichwill affect the functional performance of the hydrogel. The functionalperformance of the hydrogel material includes its ultrasound contrast,MRI contrast, swelling kinetics, swell ratio at equilibrium, mechanicalproperties (dry and swollen state), biocompatibility, degradability,processability, manufacturability, compatibility within the largermarker construct, and even radiopacity. These performance parameters arerelated to physical properties of the hydrogel such as the solidcontent, the crosslink density, and the molecular weight betweencrosslinks. In turn, these may be tuned by adjusting the hydrogelmonomer content, relative ratio of monomers (in the case of aco-polymer), the molecular weight of the starting materials, theinitiator content, the curing time/temperature/UV dose, or additivessuch as plasticizers or porogens. For example, with a PVP hydrogelprepared by direct UV crosslinking, the higher the molecular weight ofthe starting material, the greater the ultrasound contrast of thehydrogel. This is due to increased molecular weight between crosslinks,which allows for a looser polymer network to form, which allows forgreater equilibrium water content.

The majority of commercially available biopsy markers employ a metalliccomponent for radiographic contrast. These may be in the form of metaltubing, wires or coils, which present a limited number of shapes thatmay be obtained without complex manufacturing, or in the form ofmicro-machined shapes, which can be expensive to produce on a largescale. Use of a radiopacifier loaded polymer as the radiopaque elementin the above-described embodiments may allow for such designs to beinjection molded or extruded into a variety of shapes in a morecost-effective manner.

In one embodiment, the radiopaque polymer may be PMMA loaded with bariumsulfate, specifically employing a modified formulation of commerciallyavailable bone cement, KYPHON HV-R, supplied by Medtronic. Modifiedformulations may be generated from the starting material by preparingbone cement samples with barium sulfate concentrations ranging from 30%(unmodified base material) to 70% by weight. As the barium sulfateconcentration increases, the physical integrity of the final materialdecreases and the x-ray contrast of the PMMA formulations increases. At70% wt/wt concentration of barium sulfate the PMMA is qualitativelyobserved to be brittle in nature. A 60% wt/wt concentration of bariumsulfate may be preferable for preparation of radiopaque elements in thegel mesh marker 200 and the swelling bead marker 500. The PMMA markerloaded with 60% barium sulfate may achieve qualitatively similarradiographic contrast at a fraction of the size of a commerciallyavailable PEKK marker. This may allow for overall miniaturization of thePMMA marker and deployment through smaller gauge delivery devices.

A secondary benefit of the PMMA as a carrier material for theradiopacifier may be the presence of acrylate groups on the surface ofthe material. For the hydrogel systems studied here, which are partiallyformed by crosslinking which occurs at the acrylate end groups of thePEGDA chains, the acrylate groups on the surface of the PMMA radiopaquemarker can react with the hydrogel and form covalent crosslinks,resulting in a strong bond between the two materials in the case of theswelling bead embodiment. Such a reaction would not be possible on manyother surfaces (e.g., Nitinol, titanium) without complex surfacemodification.

In another embodiment, the radiopaque element may be aradiopacifier-loaded fiber. The advantage of this form is that for wovenor braided constructs, such as the gel mesh, curly fry, or shape memoryembodiments, a radiopaque polymer fiber may be incorporated into thelarger marker in a patterned form to provide a unique radiographic shapefor marker identification. The radiopacifier loaded fiber may be aDyneema RP dtex 135 TS1000 UHMWPE fiber loaded with 17-23% bismuthtrioxide by weight.

All of the markers are identifiable under three imaging modalities—ultrasound, x-ray, and MRI. Under ultrasound, the markers are similarin that the hydrogel component appears as a dark region due to the highwater content. The gel mesh marker 200 appears different in that themesh 202 appears as a hyperechoic outline around a thin layer of thehydrogel 204, though the thickness of the hydrogel 204 can be tuned byadjusting the geometry/elasticity of the mesh 202 or the swellingpressure of the hydrogel 204. The mesh form has a “candy wrapper”appearance. The swelling bead marker 500 appears as a hypoechoiccylinder surrounding the hyperechoic radiopaque element 506. The smoothsurfaces of the swelling bead marker 500 give it a man-made appearance.The Nitinol cage 402 in the shape memory marker 400 appears as ahyperechoic outline around the hydrogel hypoechoic core 404, similar tothe gel mesh marker 200. The Nitinol cage has a distinct ultrasoundcontrast (without any posterior acoustic shadowing) making it to beeasily identified by either an expert radiologist and also for peoplewith limited knowledge in this area. The curly fry marker 300 is moredifficult to identify under ultrasound due to the complex structure, butin the proper position, a hypoechoic outline (hydrogel) can be seenaround the hyperechoic mesh. Minor shadowing is observed for the gelmesh marker 200 and curly fry marker 300. All markers are located inx-ray images by bright white (x-ray absorbing) regions. The shape memorymarker 400 is different from the other markers under x-ray, as theentire marker is viewed in the images. The Nitinol cage 402 appearsdistinct, with the crimp beads 406 showing as larger bright regions. Thesmall diameter of the Nitinol tubing/wire, the Nitinol tubing/wireorientation, the picks per inch (or porosity of the Nitinol cage)prevent the contrast from masking tissue behind the shape memory markerpermanently 400. The other markers only have a radiopaque element in thecenter or at one end of the marker, but still the contrast is sufficientfor localizing the markers.

Under T2 weighted MRI images, the markers appear similar in that thehydrogel component appears as a bright region due to the high signalfrom the water content. The gel mesh marker 200 and shape memory marker400 are slightly different, as they have dark regions/outlinessurrounding the hydrogel due to the polyester mesh 202 and Nitinol cage402. The curly fry marker 300 also appears unique due to the hollow corewithin the helical structure. The hydrogel appears bright, while thevoid space within the marker shows as a dark region. True “voids” may begradually filled by tissue ingrowth after implantation, and this featureof the ultrasound contrast will gradually decrease in magnitude,ultimately disappearing. Under T1 weighted MRI images, the hydrogelcomponents of the markers appear as dark shapes.

Although particular embodiments of the disclosed inventions have beenshown and described, it will be understood that this is not intended tolimit the disclosed inventions to the preferred embodiments, and it willbe obvious to those skilled in the art that various changes andmodifications may be made without departing from the scope of thepresent inventions, which are intended to cover alternatives,modifications, and equivalents of the disclosed embodiments, as definedby the claims.

1. A remotely detectable marker for implantation in a targeted sitewithin a patient's body from which tissue has been removed, the markercomprising: a radiopaque element having a distinguishing pattern forunique identification under x-ray imaging; and a non-palpable bodycoupled to the radiopaque marker, the body comprised of a substantiallydehydrated material in a pre-deployment configuration, wherein the bodyis configured to expand between 5 and 100 percent of its pre-deploymentvolume in approximately 30 to 60 minutes when exposed to fluid, and toremain substantially physically stable when implanted within thetargeted site for at least approximately 52 weeks, wherein the body isconfigured to reflect ultrasound in a way that the body is recognizableas being artificial and is distinguishable from the radiopaque marker,and wherein the radiopaque element comprises a braided, woven or meshstructure defining an interior region, and wherein the body is containedwithin the interior region of the radiopaque element.
 2. (canceled) 3.The marker of claim 1, wherein the radiopaque element is metallic. 4.The marker of claim 1, wherein the radiopaque element is polymeric. 5.The marker of claim 4, wherein the radiopaque element comprises PMMA orultra-high molecular weight polyethylene (UHMWPE) compounded with a radiopacifier.
 6. The marker of claim 5, wherein the radiopaque elementcomprises PMMA that is loaded with approximately 30 percent toapproximately 70 percent barium sulfate by weight.
 7. The marker ofclaim 6 wherein the PMMA is loaded with approximately 60 weight percentbarium sulfate.
 8. The marker of claim 5, wherein the radiopaque elementcomprises PMMA that is loaded with approximately 17 percent toapproximately 23 percent bismuth trioxide by weight.
 9. The marker ofclaim 8, wherein the PMMA comprises approximately 20 weight percentbismuth trioxide.
 10. The marker of claim 5, wherein the PMMA isconfigured to achieve similar radiographic contrast as PEKK at a smallervolume than PEKK.
 11. The marker of claim 1, wherein the body is madeout of a hydrogel configured minimize a specular appearance underultrasound when hydrated.
 12. (canceled)
 13. The marker of claim 11,wherein the radiopaque element comprises PMMA, and wherein the PMMA andhydrogel are configured to form covalent crosslinks.
 14. The marker ofclaim 11, wherein the body comprises one or more of pHEMA, PVP, PEGDAand PVA.
 15. (canceled)
 16. The marker of claim 1, wherein theradiopaque element is made from a shape memory material. and/or asuperelastic material, and/or a radiopacifier-loaded fiber. 17.(canceled)
 18. The marker of claim 1, wherein the body comprises a firstlayer fixedly coupled to a second layer, the first and second layerseach having a proximal end, wherein the respective proximal ends of thefirst and second layers are substantially aligned, the first layercomprising a thermoplastic and the second layer comprising of asubstantially dehydrated material that swells upon contact with fluid tocause the second layer to transition to a post-deployment configuration,the post-deployment configuration having a distinguishing pattern. 19.(canceled)
 20. The marker of claim 18, wherein the second layer is madeout of shape memory thermoplastic.
 21. The marker of claim 1, whereinthe body comprises a superabsorbent polymer contained in a polymer mesh.22-25. (canceled)
 26. A remotely detectable marker for implantation in atargeted site within a patient's body from which tissue has beenremoved, the marker comprising: a radiopaque element having adistinguishing pattern for unique identification under x-ray imaging;and a non-palpable body coupled the radiopaque marker, the bodycomprised of a substantially dehydrated material in a pre-deploymentconfiguration, wherein the body has a swell ratio of 100-1000 wt/wt whenexposed to fluid for approximately 30 to 60 minutes, and is configuredto remain substantially physically stable when implanted within thetargeted site for at least approximately 52 weeks; and wherein the bodyis configured to reflect ultrasound in a way that the body isrecognizable as being artificial and is distinguishable from theradiopaque marker, and wherein the radiopaque element comprises abraided, woven or mesh structure defining an interior region, andwherein the body is contained within the interior region of theradiopaque element.
 27. (canceled)
 28. The marker of claim 26, whereinthe body has a nominal maximum swelling in the form of a volumetricchange of up to approximately 8000%.
 29. The marker of claim 26, whereinthe radiopaque element comprises PMMA that is loaded with approximately30 percent to approximately 70 percent barium sulfate by weight.
 30. Themarker of claim 26, wherein the radiopaque element comprises PMMA thatis loaded with approximately 17 percent to approximately 23 percentbismuth trioxide by weight.
 31. The marker of claim 26, wherein the bodyis made out of a hydrogel configured minimize a specular appearanceunder ultrasound when hydrated.
 32. (canceled)
 33. The marker of claim26, wherein the radiopaque element comprises PMMA, and wherein the PMMAand hydrogel are configured to form covalent crosslinks.
 34. The markerof claim 26, wherein the body comprises one or more of pHEMA, PVP, PEGDAand PVA.
 35. (canceled)
 36. The marker of claim 26, wherein theradiopaque element is made from a shape memory material. and/or asuperelastic material, and/or a radiopacifier-loaded fiber. 37.(canceled)
 38. The marker of claim 26, wherein the body comprises afirst layer fixedly coupled to a second layer, the first and secondlayers each having a proximal end, wherein the respective proximal endsof the first and second layers are substantially aligned, the firstlayer comprising a thermoplastic and the second layer comprising of asubstantially dehydrated material that swells upon contact with fluid tocause the second layer to transition to a post-deployment configuration,the post-deployment configuration having a distinguishing pattern. 39.(canceled)
 40. The marker of claim 38, wherein the second layer is madeout of shape memory thermoplastic.
 41. The marker of claim 26, whereinthe body comprises a superabsorbent polymer contained in a polymer mesh.42-44. (canceled)